Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study

INTRODUCTION: Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1-3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam. METHODS: Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6 months and 60 years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2 years of treatment. RESULTS: A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0 years (1-60 years) and 39.1 kg (9.2-108.9 kg), respectively. About 63% of patients aged 2-60 years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale-Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles. CONCLUSIONS: The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients

Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study

Introduction: Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1-3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam. Methods: Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6 months and 60 years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2 years of treatment. Results: A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0 years (1-60 years) and 39.1 kg (9.2-108.9 kg), respectively. About 63% of patients aged 2-60 years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale-Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles. Conclusions: The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients

Benefits of glucocorticoids in non-ambulant boys/men with Duchenne muscular dystrophy: A multicentric longitudinal study using the Performance of Upper Limb test

The aim of this study was to establish the possible effect of glucocorticoid treatment on upper limb function in a cohort of 91 non-ambulant DMD boys and adults of age between 11 and 26 years. All 91 were assessed using the Performance of Upper Limb test. Forty-eight were still on glucocorticoid after loss of ambulation, 25 stopped steroids at the time they lost ambulation and 18 were GC naive or had steroids while ambulant for less than a year. At baseline the total scores ranged between 0 and 74 (mean 41.20). The mean total scores were 47.92 in the glucocorticoid group, 36 in those who stopped at loss of ambulation and 30.5 in the naive group (p <0.001). The 12-month changes ranged between -20 and 4 (mean -4.4). The mean changes were -3.79 in the glucocorticoid group, -5.52 in those who stopped at loss of ambulation and -4.44 in the naive group. This was more obvious in the patients between 12 and 18 years and at shoulder and elbow levels. Our findings suggest that continuing glucocorticoids throughout teenage years and adulthood after loss of ambulation appears to have a beneficial effect on upper limb function. (C) 2015 The Authors. Published by Elsevier B.V

Two-year efficacy and safety of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA)

Risdiplam is an oral, survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier approved for the treatment of spinal muscular atrophy (SMA). SUNFISH (NCT02908685) Part 2, a Phase 3, randomized, double-blind, placebo-controlled study, investigated the efficacy and safety of risdiplam in type 2 and non‑ambulant type 3 SMA. The primary endpoint was met: a significantly greater change from baseline in 32-item Motor Function Measure (MFM32) total score was observed with risdiplam compared with placebo at month 12. After 12 months, all participants received risdiplam while preserving initial treatment blinding. We report 24-month efficacy and safety results in this population. Month 24 exploratory endpoints included change from baseline in MFM32 and safety. MFM‑derived results were compared with an external comparator. At month 24 of risdiplam treatment, 32% of patients demonstrated improvement (a change of ≥ 3) from baseline in MFM32 total score; 58% showed stabilization (a change of ≥ 0). Compared with an external comparator, a treatment difference of 3.12 (95% confidence interval [CI] 1.67-4.57) in favor of risdiplam was observed in MFM-derived scores. Overall, gains in motor function at month 12 were maintained or improved upon at month 24. In patients initially receiving placebo, MFM32 remained stable compared with baseline (0.31 [95% CI - 0.65 to 1.28]) after 12 months of risdiplam; 16% of patients improved their score and 59% exhibited stabilization. The safety profile after 24 months was consistent with that observed after 12 months. Risdiplam over 24 months resulted in further improvement or stabilization in motor function, confirming the benefit of longer-term treatment

Reliability of the Performance of Upper Limb assessment in Duchenne muscular dystrophy

Abstract The Performance of Upper Limb was specifically designed to assess upper limb function in Duchenne muscular dystrophy. The aim of this study was to assess (1) a cohort of typically developing children from the age of 3 years onwards in order to identify the age when the activities assessed in the individual items are consistently achieved, and (2) a cohort of 322 Duchenne children and young adults to establish the range of findings at different ages. We collected normative data for the scale validation on 277 typically developing subjects from 3 to 25 years old. A full score was consistently achieved by the age of 5 years. In the Duchenne cohort there was early involvement of the proximal muscles and a proximal to distal progressive involvement. The scale was capable of measuring small distal movements, related to activities of daily living, even in the oldest and weakest patients. Our data suggest that the assessment can be reliably used in both ambulant and non ambulant Duchenne patients in a multicentric setting and could therefore be considered as an outcome measure for future trials

Assessment of the validity and reliability of the 32-item Motor Function Measure in individuals with Type 2 or non-ambulant Type 3 spinal muscular atrophy.

The 32-item Motor Function Measure (MFM32) is an assessment of motor function, and its measurement properties were established in a broad neuromuscular disease population. This study sought to investigate the reliability, validity, and ability to detect change of MFM32 in individuals with Type 2 and non-ambulant Type 3 spinal muscular atrophy (SMA). Data were used from the Phase 2 study assessing the efficacy and safety of olesoxime. A total of 110 individuals with Type 2 or 3 SMA were included in the analyses. Test-retest reliability (intraclass-correlation coefficient in global impression-defined stable individuals), internal consistency (Cronbach's alpha), convergent validity (Spearman rank order correlations with other measures), known-groups validity (analysis of covariance comparing Hammersmith Functional Motor Scale -defined groups), and ability to detect change (analysis of covariance comparing global impression-defined groups) were calculated. Strong evidence of test-retest reliability (intraclass-correlation coefficient = 0.93-0.95), internal consistency (Cronbach's alpha = 0.89), convergent validity (Hammersmith Functional Motor Scale: rho = 0.87; forced vital capacity: rho = 0.61), known-groups validity (all p<0.0001), and ability to detect change (all p<0.001) were demonstrated. These results provide evidence of the MFM32's measurement properties, supporting its use in longitudinal research in individuals with Type 2 and non-ambulant Type 3 SMA

Validity and Reliability of the 32-Item Motor Function Measure in 2- to 5-Year-Olds with Neuromuscular Disorders and 2- to 25-Year-Olds with Spinal Muscular Atrophy

Abstract Introduction To investigate the validity and reliability of the 32-item Motor Function Measure (MFM32) in individuals with neuromuscular disorders (NMD), including spinal muscular atrophy (SMA), aged 2–5 years, and in non-ambulant individuals with Types 2 or 3 SMA, aged 2–25 years. Methods Test–retest reliability (intraclass correlation coefficient [ICC]), internal consistency (Cronbach’s alpha [α]), convergent validity (Spearman rank-order correlations), and known-groups validity (analysis of covariance comparing groups defined by the Clinical Global Impression of Severity [CGI-S] scale and Vignos grade) were calculated. The analysis was performed on a dataset provided by Hospices Civils De Lyon, extracted from the multinational MFM32 database. A total of 165 individuals were included in the analyses, of whom 84 were in the NMD group (aged 2–5 years) and 81 were in the SMA group (aged 2–25 years). Results Strong evidence of test–retest reliability (ICC: 2- to 5-years’ population = 0.94–0.95; 2- to 25-years’ population = 0.97), internal consistency (Cronbach’s α: 2- to 5-years’ population = 0.96; 2- to 25-years’ population = 0.95), convergent validity (2- to 5-years’ population: CGI-S rho = − 0.84, Vignos grade rho = − 0.79; 2- to 25-years’ population: CGI-S rho = − 0.49), and known-groups validity (all P < 0.001) were demonstrated. Conclusions These analyses provide supportive evidence of the validity and reliability of the MFM32 in younger individuals with NMDs, aged 2–5 years, and in non-ambulant individuals with Types 2 or 3 SMA, aged 2–25 years, supporting the use of the MFM32 across a wide age range

Systematic Literature Review of the Natural History of Spinal Muscular Atrophy: Motor Function, Scoliosis, and Contractures.

BACKGROUND AND OBJECTIVES Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder associated with continuous motor function loss and complications such as scoliosis and contractures. Understanding the natural history of SMA is key to demonstrating the long-term outcomes of SMA treatments. This study reviews the natural history of motor function, scoliosis, and contractures in patients with SMA. METHODS Electronic databases were searched from inception to June 27, 2022 (Embase, MEDLINE, and Evidence-Based Medicine Reviews). Observational studies, case-control studies, cross-sectional studies, and case series reporting on motor function (i.e., sitting, standing, and walking ability), scoliosis, and contracture outcomes in patients with Types 1-3 SMA were included. Data on study design, baseline characteristics, and treatment outcomes were extracted. Datasets were generated from studies that reported Kaplan-Meier (KM) curves and pooled to generate overall KM curves. RESULTS Ninety-three publications were included, of which 68 reported on motor function. Of these, 10 reported KM curves (three on the probability of sitting in patients with Types 2 and 3 SMA, and eight on the probability of walking/ambulation in patients with Type 3 SMA). The median time to loss of sitting (95% confidence interval [CI]) was 14.5 years (14.1-31.5) for the Type 2 SMA sitter population (their maximum ability was independent sitting). The median time to loss of ambulation (95% CI) was 13.4 years (12.5-14.5) for Type 3a SMA (disease onset at age <3 years) and 44.2 years (43.0-49.4) for Type 3b SMA (disease onset at age ≥3 years). Studies including scoliosis and contracture outcomes mostly reported non-time-to-event data. DISCUSSION Results demonstrate that a high degree of motor function loss is inevitable, affecting patients of all ages. Additionally, data suggest that untreated patients with Types 2 and 3 SMA remain at risk of losing motor milestones during late adulthood, and patients with Types 3a and 3b SMA are at risk of loss of ambulation over time. These findings support the importance of stabilization of motor function development even at older ages. Natural history data are key for the evaluation of SMA treatments as they contextualize the assessment of long-term outcomes

Prognostic Factors and Treatment-Effect Modifiers in Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease characterized by loss of motor neurons and muscle atrophy. Untreated infants with type 1 SMA do not achieve major motor milestones, and death from respiratory failure typically occurs before 2 years of age. Individuals with types 2 and 3 SMA exhibit milder phenotypes and have better functional and survival outcomes. Herein, a systematic literature review was conducted to identify factors that influence the prognosis of types 1, 2, and 3 SMA. In untreated infants with type 1 SMA, absence of symptoms at birth, a later symptom onset, and a higher survival of motor neuron 2 (SMN2) copy number are all associated with increased survival. Disease duration, age at treatment initiation, and, to a lesser extent, baseline function were identified as potential treatment-modifying factors for survival, emphasizing that early treatment with disease-modifying therapies (DMT) is essential in type 1 SMA. In patients with types 2 and 3 SMA, factors considered prognostic of changes in motor function were SMN2 copy number, age, and ambulatory status. Individuals aged 6-15 years were particularly vulnerable to developing complications (scoliosis and progressive joint contractures) which negatively influence functional outcomes and may also affect the therapeutic response in patients. Age at the time of treatment initiation emerged as a treatment-effect modifier on the outcome of DMTs. Factors identified in this review should be considered prior to designing or analyzing studies in an SMA population, conducting population matching, or summarizing results from different studies on the treatments for SMA

How does risdiplam compare with other treatments for Types 1-3 spinal muscular atrophy: a systematic literature review and indirect treatment comparison

Aim: To conduct indirect treatment comparisons between risdiplam and other approved treatments for spinal muscular atrophy (SMA). Patients &amp; methods: Individual patient data from risdiplam trials were compared with aggregated data from published studies of nusinersen and onasemnogene abeparvovec, accounting for heterogeneity across studies. Results: In Type 1 SMA, studies of risdiplam and nusinersen included similar populations. Indirect comparison results found improved survival and motor function with risdiplam versus nusinersen. Comparison with onasemnogene abeparvovec in Type 1 SMA and with nusinersen in Types 2/3 SMA was challenging due to substantial differences in study populations; no concrete conclusions could be drawn from the indirect comparison analyses. Conclusion: Indirect comparisons support risdiplam as a superior alternative to nusinersen in Type 1 SMA.</p